Transcriptional and Epigenetic Consequences of DMSO Treatment on HepaRG Cells

Cells. 2022 Jul 26;11(15):2298. doi: 10.3390/cells11152298.

Abstract

Dimethyl sulfoxide (DMSO) is used to sustain or favor hepatocyte differentiation in vitro. Thus, DMSO is used in the differentiation protocol of the HepaRG cells that present the closest drug-metabolizing enzyme activities to primary human hepatocytes in culture. The aim of our study is to clarify its influence on liver-specific gene expression. For that purpose, we performed a large-scale analysis (gene expression and histone modification) to determine the global role of DMSO exposure during the differentiation process of the HepaRG cells. The addition of DMSO drives the upregulation of genes mainly regulated by PXR and PPARα whereas genes not affected by this addition are regulated by HNF1α, HNF4α, and PPARα. DMSO-differentiated-HepaRG cells show a differential expression for genes regulated by histone acetylation, while differentiated-HepaRG cells without DMSO show gene signatures associated with histone deacetylases. In addition, we observed an interplay between cytoskeleton organization and EMC remodeling with hepatocyte maturation.

Keywords: DMSO; HepaRG cells; gene expression; hepatic differentiation; histone modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dimethyl Sulfoxide* / metabolism
  • Dimethyl Sulfoxide* / pharmacology
  • Epigenesis, Genetic*
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Hepatocytes* / drug effects
  • Hepatocytes* / metabolism
  • Humans
  • Liver / metabolism
  • PPAR alpha / metabolism

Substances

  • HNF1A protein, human
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • PPAR alpha
  • Dimethyl Sulfoxide

Grants and funding

This work was supported and funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), the University of Rennes, the INSERM/Japan Society for the Promotion of Science cooperation programme, the Seventh Framework Programme (FP7) LIV-ES (grant no. 223317), the «Contrat Plan Etat Région», the «Conseil Regional de Bretagne». This study was also funded by the EU (NOTOX, grant no. FP7 267038) and the German Federal Ministry of Education and Research (BMBF) under 01EK1604A-D (StemNet project).